Do Mice From The Same Strain Have Identical Genomes?

Question

[Nick]

I am a bioinformatician, not a biologist hence my question may appear very naive. Here is my case:

I was given exome data of several transgenic mice. Some have been additionally treated to develop certain types of tumors, a single transgenic mice has been kept as control. I have been asked to look for tumor genome variation.

Most studies on tumor genome variation I know of use paired samples (a sample from the tumor and a control from a healthy tissue of the same animal or individual). This is still not trivial as the tumor is often a mix of different subclonal populations but, at least, there are plenty of bioinformatics tools that try to elucidate the tumor mutations vs the healthy tissue and all the differences which are found are atributed to the tumor.

What I don't know is whether I can treat the different transgenic mice from the same strain as having the same genome, i.e. attribute any differences between genome of the tumor of animal A and the genome of healthy animal B to the tumor alone, rather than to genome variation between A and B?

[Fabio Marroni]

The easiest thing would be to have 2 mice from strain A and 2 from strain B and require that the two mice form A are different from the two mice from B strain. If you only have one animal per strain you can never know if variants and tumor have a causal correlation.

[Nick]

Indeed, testing on two different strains would be better - but I am still left wondering whether using two mice of the same strain as a case and control pair is equivalent to having a set of paired samples from the same animal.

[Neilfws]

Don't let anyone tell you that bioinformaticians are not biologists.

Answer 1

[Ido Tamir]

This is more a biology question. However I do think, this site should open its scope a bit.

http://research.jax.org/grs/type/inbred/index.html Mouse strains (and other model organism strains) are inbred over many generations, making them homozygous for basically all loci. The descendents of a mouse cross are therefore as similar to clones as one can get with sexual reproduction. If the mice do indeed come from the same strain (and not from different substrains) they are identical. Don't forget there are also age, sex etc.. differences possible.

One control mouse sounds strange. I hope I misunderstood something.

[Nick]

If all transgenic mice are considered to have identical genomes and if one looks at the genomic differences between the tumor of mouse A and the healthy tissue of mouse B (of the same strain) than having one control shall be enough. If no biological variation exists all the observed discrepancies shall be ascribed to the tumor. But it all hinges on the assumption of identical genomes.

[Nick]

On a related note, the assumption of identical genomes makes the control redundant as many mouse strains have their genomes/exomes published. The only reason to include a control would be to account for any variation resulting from the specific library prep and the sequencing run.

[Ido Tamir]

I was just skimming your experiment explanation and I am used to a different type of tumor experiments (like growth rates of tumors in wt vs treated). Yes it makes sense that one reference genome is enough if you compare genomes. I would definitely not rely on a published mouse strain for this.

Answer 2

[Chris Miller]

This is an (unfortunately) common setup for mouse-model projects.

The short answer is "yes, you can treat the control sample like a matched normal".

The long answer is: Yes, you can treat the control sample like a matched normal, but understand that some of the differences you detect will, in fact be differences between the mice. You'd be better off if you had several control mice so you could identify the common polymorphisms. You might also check to see if anyone has published data from this mouse strain that would allow you to construct a sort of mouse dbsnp for your strain that you could use to remove variation that is population-specific, not tumor-specific.

[David Quigley]

Many transgenic mice have mixed backgrounds. Others started out on one strain (typically 129) and have been crossed onto another strain, with the degree of purity depending on the number of backcross generations. The best approach with transgenics is to use several untreated controls from the same litters as your treated samples.

Answer 3

[Nick]

I cross-posted the same question on seqanswers - and got this excellent answer: http://seqanswers.com/forums/showpost.php?p=109867&postcount=2